Ofatumumab in combination with glucocorticoids for primary therapy of chronic graft-versus-host disease: phase I trial results.

Standard primary therapy for chronic graft-versus-host disease (GVHD) is incompletely effective. Based on biologic insights implicating pathogenic B cells, we conducted a phase I trial examining the combination of standard (1 mg/kg/day prednisone) glucocorticoid therapy with ofatumumab, a humanized anti-CD20 monoclonal antibody, for primary chronic GVHD therapy. Patients ages ≥ 18 with National Institutes of Health Consensus moderate-to-severe chronic GVHD newly requiring 1 mg/kg/day prednisone were treated at 3 escalating dose levels (300 mg, 700 mg, and 1000 mg) of i.v. ofatumumab on days 1 and 14 of initial glucocorticoid therapy. Dose-limiting toxicity (DLT) was defined by grade 4 infusion reactions, related grade 4 constitutional symptoms, related grade ≥ 3 organ toxicities, or grade 4 neutropenia lasting > 14 days. A total of 12 patients (median age 54; range, 25 to 72) were treated (dose level 1: n = 3; level 2: n = 3; level 3: n = 6). At enrollment, overall chronic GVHD was moderate (n = 7) or severe (n = 5), with diverse organ involvement (skin: n = 8; mouth: n = 8; eye: n = 8; lung: n = 4; gastrointestinal: n = 3; liver: n = 5; genital: n = 2; joint/fascia: n = 5). Infusion of ofatumumab was well tolerated, and no DLT was observed. From the total number of adverse events (n = 29), possibly related adverse events (n = 4) included grade 1 fatigue, grade 1 transaminitis, and 2 infusion reactions (grades 2 and 3). Infectious complications were expected, and there were no cases of hepatitis B reactivation or progressive multifocal leukoencephalopathy. Ofatumumab in combination with prednisone is safe and a phase II examination of efficacy is ongoing.

Prolonged sirolimus administration after allogeneic hematopoietic cell transplantation is associated with decreased risk for moderate-severe chronic graft-versus-host disease.

Effective pharmacological strategies employed in allogeneic hematopoietic cell transplantation should prevent serious chronic graft-versus-host disease and facilitate donor-recipient immune tolerance. Based on demonstrated pro-tolerogenic activity, sirolimus (rapamycin) is an agent with promise to achieve these goals. In a long-term follow-up analysis of a randomized phase II trial comparing sirolimus/tacrolimus versus methotrexate/tacrolimus for graft-versus-host disease prevention in matched sibling or unrelated donor transplant, we examined the impact of prolonged sirolimus administration (≥ 1 year post-transplant). Median follow-up time for surviving patients at time of this analysis was 41 months (range 27-60) for sirolimus/tacrolimus and 49 months (range 29-63) for methotrexate/tacrolimus. Sirolimus/tacrolimus patients had significantly lower National Institutes of Health Consensus moderate-severe chronic graft-versus-host disease (34% vs. 65%; P=0.004) and late acute graft-versus-host disease (20% vs. 43%; P=0.04). While sirolimus/tacrolimus patients had lower prednisone exposure and earlier discontinuation of tacrolimus (median time to tacrolimus discontinuation 368 days vs. 821 days; P=0.002), there was no significant difference in complete immune suppression discontinuation (60-month estimate: 43% vs. 31%; P=0.78). Prolonged sirolimus administration represents a viable approach to mitigate risk for moderate-severe chronic and late acute graft-versus-host disease. Further study of determinants of successful immune suppression discontinuation is needed.

A phase 2 trial of the histone deacetylase inhibitor panobinostat for graft-versus-host disease prevention.

Immunomodulatory properties of histone deacetylase inhibitors represent a reasonable approach for acute graft-versus-host disease (aGVHD) prevention. We report a phase 2 trial evaluating panobinostat (PANO) administered over 26 weeks, starting on day -5 (5 mg orally 3 times a week) with tacrolimus initiated on day -3 plus sirolimus on day -1, with a median patient age of 58 years (range, 19-72 years) (n = 38). Donor source consisted of HLA 8/8-matched donors, related (n = 13) or unrelated (n = 25), using granulocyte colony-stimulating factor-stimulated peripheral blood stem cells. Myeloablative (n = 18) or reduced-intensity (n = 20) conditioning regimens were used for patients with acute myeloid leukemia (n = 17), myelodysplastic syndrome (n = 13), or other malignancies (n = 8). The cumulative incidence of aGVHD II-IV by day 100 was 18.4% (90% confidence interval [CI], 9.4% to 29.9%). Cumulative incidence of chronic GVHD at 1 year was 31.6% (90% CI, 19.5% to 44.3%). Adverse events related to PANO were thrombocytopenia (n = 5), leukopenia (n = 6), gastrointestinal toxicity (n = 3), rash (n = 4), renal failure/peripheral edema (n = 1), and periorbital edema (n = 1). At 1 year, overall survival was 89.5% (90% CI, 81.6% to 98.0%), relapse-free survival was 78.9% (90% CI, 68.8% to 90.6%), nonrelapse mortality was 2.6% (90% CI, 0.3% to 9.9%), and GVHD relapse-free survival was 60.5% (90% CI, 48.8% to 75.1%). PANO hits histone 3 as early as day 15 in CD8, CD4 and T regs. In conclusion, PANO combination met the primary study end point for aGVHD prevention and warrants further testing. This trial was registered at www.clinicaltrials.gov as #NCT02588339.

Phase I trial of histone deacetylase inhibitor panobinostat in addition to glucocorticoids for primary therapy of acute graft-versus-host disease.

Glucocorticoids for primary therapy of acute GVHD have limited responses. A phase I/II trial tested 4 weeks of deacetylase inhibitor panobinostat started within 48 h of glucocorticoids (1 mg/kg/day prednisone or equivalent) as primary treatment for patients with either classic acute GVHD (n = 16) or acute GVHD overlapping with chronic (n = 6). Four patients received 2.5 mg/m2 IV three times a week (TIW). Subsequent to discontinuation of IV panobinostat, patients received oral doses (PO). Two patients treated with 10 mg TIW (PO level 1) had progressive GVHD, after which patients were treated with 5 mg TIW (PO level -1; n = 16); 31/41 adverse events were possibly related, including thrombocytopenia (n = 13), leukopenia (n = 7), hypercholesterolemia (n = 3), hypertriglyceridemia (n = 5), anemia (n = 1), fatigue (n = 1), and hepatobiliary disorder (n = 1). GVHD responses were complete (n = 12) or partial (n = 3), with 1 progression at PO level -1. T-regulatory cells increased at day 8, CD4/CD8 and monocytes exhibited enhanced H3 acetylation, and CD4 or CD8 numbers remained unchanged with a decreased interleukin 12p40 plasma level. Panobinostat in combination with prednisone is safe and warrants further testing in GVHD.